Alteplase For Treating Acute Ischaemic Stroke PDF 82600551992005

Alteplase for treating acute ischaemic
strok
stroke
e
Technology appraisal guidance

Published: 26 September 2012
nice.org.uk/guidance/ta264
NICE 2012. All rights reserved.

Alteplase for treating acute ischaemic stroke (TA264)
Your responsibility
The recommendations in this guidance represent the view of NICE, arrived at after careful
consideration of the evidence available. When exercising their judgement, health professionals are
expected to take this guidance fully into account, alongside the individual needs, preferences and
values of their patients. The application of the recommendations in this guidance are at the
discretion of health professionals and their individual patients and do not override the
responsibility of healthcare professionals to make decisions appropriate to the circumstances of
the individual patient, in consultation with the patient and/or their carer or guardian.
Commissioners and/or providers have a responsibility to provide the funding required to enable
the guidance to be applied when individual health professionals and their patients wish to use it, in
accordance with the NHS Constitution. They should do so in light of their duties to have due regard
to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce
health inequalities.
NICE 2012. All rights reserved. Page 2 of 37

Contents
1 Guidance .......................................................................................................................................................................... 4
2 The technology ............................................................................................................................................................. 5
3 The manufacturer's submission.............................................................................................................................. 6
4 Consideration of the evidence ................................................................................................................................ 15
Summary of Appraisal Committee's key conclusions ...................................................................................................... 19
5 Implementation............................................................................................................................................................. 26
6 Recommendations for further research ............................................................................................................. 27
7 Related NICE guidance............................................................................................................................................... 28
8 Review of guidance ...................................................................................................................................................... 29
Appendix A: Appraisal Committee members and NICE project team ........................................................ 30
A Appraisal Committee members ........................................................................................................................................... 30
B NICE project team ..................................................................................................................................................................... 32
Appendix B: Sources of evidence considered by the Committee ................................................................. 33
Changes after publication............................................................................................................................................. 35
About this guidance......................................................................................................................................................... 36

This guidance replaces TA122.
1 Guidance
This guidance replaces NICE technology appraisal guidance 122 (published in June 2007). For
details see About this guidance.
1.1 Alteplase is recommended within its marketing authorisation for treating acute
ischaemic stroke in adults if:
treatment is started as early as possible within 4.5 hours of onset of stroke symptoms,
and
intracranial haemorrhage has been excluded by appropriate imaging techniques.

2 The technology
2.1 Alteplase (Actilyse, Boehringer Ingelheim) is a tissue plasminogen activator

manufactured by recombinant DNA technology. It activates the production of
plasmin from its precursor plasminogen. Plasmin is an enzyme that degrades
fibrin clots. The aim of treatment is to reduce the impact of ischaemia by
restoring blood flow through the occluded (blocked) artery. A UK marketing
authorisation for alteplase to treat acute ischaemic stroke within 3 hours of the
onset of symptoms was granted in September 2002. On 14 March 2012 the
manufacturer received approval from the Medicines and Healthcare products
Regulatory Agency extending the use of alteplase to within 4.5 hours of the
onset of symptoms. The current marketing authorisation states that treatment
must be started as early as possible within 4.5 hours after onset of stroke
symptoms and after exclusion of intracranial haemorrhage by appropriate
imaging techniques.
2.2 The summary of product characteristics lists the following adverse reactions for
alteplase: haemorrhage (intracranial and gastrointestinal), recurrent ischaemia
or angina, hypotension, heart failure, pulmonary oedema and reperfusion
arrhythmias. For full details of adverse reactions and contraindications, see the
summary of product characteristics.
2.3 The cost of alteplase is 135 per 10-mg pack, 180 per 20-mg pack and 300
per 50-mg pack (excluding VAT; 'British national formulary' [BNF] edition 63).
The cost per course of treatment depends on the body weight of the patient,
and can range from 300 to 600 based on a recommended dose of 0.9 mg per
kilogram of body weight. Costs may vary in different settings because of
negotiated procurement discounts.

3 The manufacturer's submission
3.1 The Appraisal Committee (appendix A) considered evidence submitted by the

manufacturer of alteplase and a review of this submission by the Evidence
Review Group (ERG; appendix B). The decision problem addressed by the
manufacturer considered whether treatment with alteplase was clinically
effective compared with standard medical care (standard medical and
supportive management that does not include alteplase) for treating acute
ischaemic stroke in adults within 4.5 hours of symptom onset, and whether
alteplase treatment was a cost-effective use of NHS resources.
3.2 The manufacturer carried out a systematic literature search, which was based
on a previously published Cochrane review ('Thrombolysis for acute ischaemic
stroke'), but restricted the search to randomised controlled trials of alteplase.
For the 0 to 3-hour treatment window, the manufacturer identified no trials
other than those included in the previous guidance on alteplase in acute
ischaemic stroke (NICE technology appraisal guidance 122) from 2007. The
trials in technology appraisal guidance 122 included NINDS (National Institute
of Neurological Disorders and Stroke) I and II, ATLANTIS ('Thrombolysis for
acute noninterventional therapy in ischaemic stroke') A and B, and ECASS (the
'European Cooperative Acute Stroke Study') II. All these trials were multicentre,
double-blinded, placebo-controlled randomised controlled trials of alteplase
administered at its licensed dose of 0.9 mg/kg. Treatment with alteplase was
administered within 3 hours (NINDS I and II), 5 hours (ATLANTIS B) or 6 hours
(ATLANTIS A, ECASS II) of onset of stroke symptoms. Patients were followed up
for outcomes for 90 days. The NINDS and ATLANTIS trials were conducted in
North America and the ECASS trial in multiple sites in Europe (including the
UK), Australia and New Zealand.
3.3 The clinical-effectiveness evidence in the manufacturer's submission focused on

the extended 3 to 4.5-hour treatment window for which the only directly
relevant trial identified by the manufacturer was ECASS III. Other trials with
data indirectly relevant to this treatment window were ATLANTIS A and B and
ECASS II, from which subgroup data specifically for the 3 to 4.5-hour window
were used by the manufacturer in sensitivity analyses. The manufacturer noted
that this involved stratifying data into subgroups that had not been specified
before randomisation. The manufacturer also identified the third International
Stroke Trial (IST-3), a randomised open-label blinded endpoint trial in which

alteplase was administered within 6 hours of symptom onset. However, the

manufacturer commented that this trial was not placebo controlled and
therefore did not meet its trial selection criteria, and that no published results
were available at the time of submission.
3.4 ECASS III was a placebo-controlled multicentre trial carried out across 130 sites
in 19 European countries. Of the 821 patients 22 were from the UK. Patients
were eligible for inclusion if aged between 18 and 80 years, diagnosed with
acute ischaemic stroke and able to receive treatment within 3 to 4.5 hours of
the onset of stroke symptoms. Before randomisation, brain imaging was used to
exclude intracranial haemorrhage. The trial randomly assigned eligible patients
to receive 0.9 mg/kg of intravenous alteplase (n=418) or placebo (n=403).
Patients were followed up for 90 days for outcomes. Baseline demographic and
disease characteristics were similar between participants in the 2 treatment
arms, but the initial severity of the stroke (as assessed by the National Institutes
of Health stroke scale [NIHSS; a 15-item quantitative measure of stroke-related
neurological impairment]) and the proportion of patients with a history of
previous stroke were both significantly higher in the placebo arm.
3.5 The primary outcome in ECASS III was the presence or absence of disability at
90 days as assessed by the modified Rankin scale, which measures the degree of
disability or dependence in people who have had a stroke and ranges from 0
(symptom free) to 6 (dead). From intention-to-treat analyses, 52.4% of patients
randomised to the alteplase treatment arm had a favourable outcome at 90 days
(a score of 0 or 1 [no significant disability]) compared with 45.2% of patients
randomised to placebo (odds ratio [OR] 1.34, 95% confidence interval [CI] 1.02
to 1.76, p=0.04). After adjustment for confounding baseline variables (identified
as being statistically significant at p<0.10) including treatment arm, NIHSS
score, smoking, time from onset of stroke to treatment, and presence or
absence of previous hypertension, alteplase remained statistically significantly
associated with a favourable outcome (OR 1.42, 95% CI 1.02 to 1.98, p=0.04).
3.6 ECASS III also reported the composite outcome of death or dependence
(defined as a score of 36 on the modified Rankin scale) at 90 days. There were
no statistically significant differences in the number of patients who were dead
or dependent between the alteplase and placebo treatment arms (33.5%
compared with 38.5%, relative risk [RR] 0.87, 95% CI 0.73 to 1.05).

3.7 The ECASS III trial also reported as a secondary endpoint a global outcome
score at 90 days, which combined a score of 01 on the modified Rankin scale, a
score of 1 on the Glasgow outcome scale (a 5-point measure of brain injury, with
1 indicating independence and 5 death), a score of 95100 on the Barthel index
(a 10-item measure of a person's daily function, with higher scores reflecting
higher function), and a score of 01 on the NIHSS. Randomisation to alteplase
was associated with a statistically significantly higher probability of achieving a
favourable global outcome score (OR 1.28, 95% CI 1.00 to 1.65, p=0.05).
3.8 The manufacturer presented a summary of adverse reactions based on

intention-to-treat analyses in the ECASS III trial at 90 days. Fatal adverse
reactions were reported for 7.7% of patients in the alteplase arm and 8.4% of
those in the placebo arm. A statistically significantly higher proportion of
patients in the alteplase arm had an intracranial haemorrhage (27.0% compared
with 17.6%, p=0.001) or a symptomatic intracranial haemorrhage (2.4%
compared with 0.3%, p=0.008) compared with the placebo arm. Three patients
(0.7%) randomised to the alteplase arm had a fatal intracranial haemorrhage.
Investigator-defined drug-related adverse reactions were reported for 23.9% of
patients in the alteplase treatment arm and 6.9% of patients in the placebo arm.
Other serious adverse reactions were reported for 25.1% of patients in the
alteplase arm and 24.6% of those in the placebo arm.
3.9 The manufacturer conducted meta-analyses to calculate the relative risks

associated with alteplase for all-cause mortality within 90 days, death or
dependence within 90 days, and symptomatic intracranial haemorrhage within
10 days for each of the 3 treatment windows (0 to 3 hours, 3 to 4.5 hours, and 0
to 4.5 hours). The manufacturer presented results from both fixed and random-
effects models. For the 0 to 3-hour window, the manufacturer used data from
ECASS II and NINDS and used the relative risks from ECASS III for the 3 to
4.5-hour window. For the 0 to 4.5-hour window, the manufacturer used data
from ECASS II (0 to 3 hours), ECASS III (3 to 4.5 hours) and NINDS (0 to 3 hours).
Heterogeneity between the 3 studies was low for the outcomes of all-cause
mortality and death or dependence, but moderate for the outcome of
symptomatic intracranial haemorrhage.
3.10 The manufacturer compared all-cause mortality at 90 days for the 2 treatment
arms. No statistically significant difference was observed between alteplase and
placebo for the 3 to 4.5-hour (RR 0.82, 95% CI 0.50 to 1.33, p=0.42), the 0 to

3-hour (RR 1.05, 95% CI 0.55 to 2.03, p=0.88) or the 0 to 4.5-hour (RR 0.89, 95%
CI 0.67 to 1.18, p=0.41) treatment windows. For the outcome of death or
dependence at 90 days, the manufacturer reported no statistically significant
difference between alteplase and placebo for the 3 to 4.5-hour window (RR
0.87, 95% CI 0.73 to 1.05, p=0.14). However, a statistically significant difference
in favour of alteplase was reported for both the 0 to 3-hour window (RR 0.81,
95% CI 0.72 to 0.92, p=0.002) and the 0 to 4.5-hour window (RR 0.83, 95% CI
0.75 to 0.92, p<0.001). For the outcome of symptomatic intracranial
haemorrhage occurring within 10 days, patients randomised to receive
alteplase within the 3 to 4.5-hour window had a statistically significant higher
risk (RR 4.82, 95% CI 1.06 to 21.87, p=0.04), with similar results for the 0 to
4.5-hour treatment window (RR 4.18, 95% CI 1.39 to 12.53, p=0.01). For the 0
to 3-hour window, the manufacturer reported a higher risk of symptomatic
intracranial haemorrhage among patients randomised to alteplase that was not
statistically significant (RR 3.94, 95% CI 0.61 to 25.47, p=0.15).
3.11 The manufacturer conducted a systematic review of published cost-

effectiveness analyses but did not identify any studies that evaluated the cost
effectiveness of alteplase for the treatment of acute ischaemic stroke within 3
to 4.5 hours of onset of symptoms. Instead, the manufacturer adapted a
published cost-effectiveness analysis (Sandercock et al., 2002) relevant to the
decision problem from the previous guidance on alteplase in acute ischaemic
stroke (NICE technology appraisal guidance 122) and used this as part of its
submission.
3.12 The manufacturer developed a Markov model simulating patients with acute
ischaemic stroke who do or do not receive alteplase within 4.5 hours of onset of
symptoms. Patients were modelled through 3 possible health states:
independent, dependent and dead. The independent state was defined by a
modified Rankin scale score of 02 and the dependent state by a modified
Rankin scale score of 35. The model had 3 time phases: from 0 to 6 months
when the model assumed the treatment effect of alteplase was complete at
90 days and maintained at 6 months; from 6 to 12 months when the model
assumed no further treatment effect; and beyond 12 months when the model
also assumed no further treatment effect from alteplase. However, beyond
12 months the model assumed that people in the dependent or independent
states could have a recurrent stroke. The model also assumed that people in the
dependent state at 12 months and beyond do not move to an independent state,

and that people in the independent state at 12 months and beyond do not move
to a dependent state unless they survive a recurrent stroke. The model assumed
a lifetime horizon with a cycle length of 6 months for the first 12 months,
followed by cycles of 12 months thereafter.
3.13 The manufacturer chose a population for the model based on SITS-MOST ('Safe
implementation of thrombolysis in stroke-monitoring study'), a European
observational study of patients receiving alteplase. The manufacturer
considered that this study population represented the mean age (68 years) and
gender distribution (39.8% female) of patients who would receive alteplase in
clinical practice in England and Wales.
3.14 For the first phase (0 to 6 months) of the manufacturer's economic model, the
size of the effect of treatment with alteplase was informed by the
manufacturer's meta-analyses for the 3 treatment windows as described in
section 3.8. For the standard treatment arm, the proportion of people in each
health state (39.53% independent, 32.56% dependent and 27.91% dead) was
informed by the Lothian stroke registry, a registry in Edinburgh, Scotland, of
1779 inpatients with suspected or confirmed stroke from 1989 to 2000. The
manufacturer also provided an alternative distribution of the proportion of
people who received standard treatment in each health state from the placebo
arm of the ECASS III trial at 90 days. This alternative distribution (61.54%
independent, 30.27% dependent and 8.19% dead) was used by the ERG in
exploratory sensitivity analyses. The manufacturer then used the relative risks
of death and death or dependence to calculate the distribution of people in the
alteplase arm across the independent, dependent and dead states at the end of
the first phase (6 months). The manufacturer used the relative risk of death to
estimate the proportion of people who would die and therefore enter the dead
state during the first phase. The proportion of people in the dependent state at
6 months was calculated as the difference between the estimated proportion of
people who were dead or dependent, and the estimated proportion who were
dead. The manufacturer assumed in the model that a symptomatic intracranial
haemorrhage had a cost impact (because it required a further diagnostic
computed tomography [CT] scan), with the health consequences being captured
in the outcome of death or dependence from the clinical trials.
3.15 For the second phase of the model (6 to 12 months), the manufacturer assumed
that people could move from the independent or dependent state to any other

health state with equal probabilities for both treatment arms. These transition
probabilities were based on the Lothian stroke registry. For the third phase of
the model (beyond 12 months), the annual risk of a recurrent stroke (0.05), and
the associated risk of mortality (0.25), were taken from the Lothian stroke
registry. To estimate the mortality risk for people who did not have another
stroke, the manufacturer took data from the Office for National Statistics life
tables for England and Wales and adjusted them upward by a factor of 2.3
(taken from the Perth Community Stroke Study) to reflect the higher mortality
rates among people who have had a stroke compared with the general UK
population.
3.16 The manufacturer conducted a literature review to identify appropriate utility

values for the independent and dependent states in the model. The
manufacturer did not identify any relevant utility values additional to those
used in NICE technology appraisal guidance 122 on alteplase in acute ischaemic
stroke within the first 3 hours after symptom onset. The manufacturer's
submission for this appraisal identified 1 trial (Dorman et al., 1997) that
collected EQ-5D utility values in a sample of 147 patients from the Lothian
stroke registry. This trial provided utility values of 0.74 (95% CI 0.69 to 0.79) for
the independent state and 0.38 (95% CI 0.29 to 0.47) for the dependent state.
The model assumed that these utility values remained fixed over time unless a
person had a recurrent stroke which resulted in dependence, and thus a move
from the independent to the dependent state.
3.17 The model included drug acquisition and administration costs as well as the
costs of acute and long-term stroke care. The cost of alteplase was based on the
mean body weight (76 kg) of patients in the 3 to 4.5-hour cohort from the SITS-
MOST trial. Based on the recommended dose of 0.9 mg/kg, the average dose
was 68.4 mg, resulting in a total estimated cost of 480 (300 per 50-mg pack
and 180 per 20-mg pack). Administration costs associated with alteplase of
1316 per patient were based on estimates of extra staff time in the trial by
Sandercock et al. (2002). For people in either treatment arm who had a
symptomatic intracranial haemorrhage, the model included a one-off cost of
100 for an additional CT scan. For all health states in the model, the
manufacturer applied annual costs specific to the state (adjusted for inflation to
2012/13 prices) adapted from a study by Youman et al. (2003), which calculated
the costs of acute events and long-term stroke care.

3.18 The manufacturer's base-case deterministic cost-effectiveness analysis for the

0 to 4.5-hour window estimated an incremental cost-effectiveness ratio (ICER)
of 2441 per quality-adjusted life year (QALY) gained for alteplase compared
with standard care (incremental costs 811; incremental QALYs 0.333). The
probabilistic cost-effectiveness analysis resulted in an ICER of 2296 per QALY
gained.
3.19 The manufacturer conducted a number of one-way sensitivity analyses on

various parameters in the model, including the relative risks associated with
alteplase of death or of death or dependence, the risk of recurrent stroke and
mortality irrespective of previous treatment, the dose of alteplase treatment,
the annual costs of care in the dependent and independent states, the cost of a
fatal stroke, and the utility values. The results of these one-way sensitivity
analyses indicated that the ICERs were robust to changes in most input
parameters, except for the relative risks of death and death or dependence for
treatment with alteplase applied in the first phase of the model. When the
manufacturer used the upper limit of the 95% confidence interval for the
relative risks of death (1.18) and death or dependence (0.92), alteplase
treatment led to a very small loss in QALYs at a decreased cost compared with
standard care, resulting in 44,342 saved per QALY lost. The manufacturer also
conducted additional deterministic sensitivity analyses, which included
different scenarios using additional clinical efficacy data from unplanned
subgroup analyses of the ATLANTIS A and B and ECASS II trials for 3 to
4.5 hours, and weighted the results based on the assumption that in UK clinical
practice a higher proportion of patients are treated during the 0 to 3-hour
window (76%) than during the 3 to 4.5-hour window (24%). Using these
analyses, alteplase either dominated placebo (that is, was both less costly and
more effective) or had an ICER below 2000 per QALY gained. Results of the
probabilistic sensitivity analysis showed that alteplase had a high probability
(above 90%) of being cost effective at a level of 20,000 to 30,000 per QALY
gained.
3.20 The manufacturer's base-case deterministic cost-effectiveness analysis for the

3 to 4.5-hour window resulted in an ICER of 6272 per QALY gained for
alteplase compared with standard care (incremental costs 2068; incremental
QALYs 0.33). The probabilistic cost-effectiveness analysis resulted in an ICER of
6169 per QALY gained. The results of the one-way sensitivity analyses were
similar to those for the 0 to 4.5-hour window, indicating that the ICERs were

robust to changes in most input parameters, except for changes in the relative
risks of death and death or dependence for treatment with alteplase. In an
additional sensitivity analysis, the manufacturer pooled 3 to 4.5-hour efficacy
data from the ECASS II and ATLANTIS trials with the ECASS III data. This
sensitivity analysis resulted in an ICER of 5631 per QALY gained for alteplase
compared with standard care.
3.21 For the 0 to 3-hour treatment window, the manufacturer presented cost-
effectiveness results similar to those presented in the previous guidance on
alteplase in acute ischaemic stroke (NICE technology appraisal guidance 122);
that is, alteplase dominated standard care, resulting in lower costs and more
QALYs for both the deterministic and the probabilistic analyses.
3.22 The ERG considered that the clinical-effectiveness evidence submitted by the
manufacturer was of good quality. The ERG noted that the patients randomised
to the alteplase arm of both the NINDS trial (which provided clinical evidence
for the 0 to 3-hour window) and the ECASS III trial had strokes that were less
severe on average, which in turn may have biased the results in favour of
alteplase. However, the manufacturer also presented adjusted analyses for the
primary outcome (disability at 90 days) from the ECASS III trial. The ERG
considered that the meta-analytical approach by the manufacturer was
appropriate. The ERG agreed with the manufacturer that data derived from
unplanned subgroup analyses from the ATLANTIS A and B and ECASS II trials, in
which treatment with alteplase was administered up to 6 hours from onset of
symptoms, should not be included in the base-case meta-analyses. The ERG also
noted that heterogeneity between the studies included in the base-case meta-
analyses for the 0 to 4.5-hour window for the outcomes of death and death or
dependence was low and not statistically significant.
3.23 The ERG commented that the manufacturer submitted an economic model that
was in line with the decision problem defined in the scope and closely adhered
to the NICE reference case requirements for economic analysis. The ERG
commented that the manufacturer provided a reasonable strategy for searching
the literature for existing cost-effectiveness studies, although it did not
explicitly state its exclusion criteria. The ERG stated that it was appropriate for
the manufacturer to conduct separate analyses for patients eligible for
treatment within the 0 to 3-hour window and the 3 to 4.5-hour window. The
ERG noted that the utility values for the dependent and independent states did

not allow for any decreases in health-related quality of life over time, which may
have overestimated the lifetime QALYs accrued in the independent state. The
ERG stated that, although this may have biased the QALY gains in favour of
alteplase, the manufacturer's economic model was not sensitive to changes in
the utility values, and so the effect of adjusting these values over time in the
model was likely to be small. The ERG noted that in the probabilistic sensitivity
analysis, the manufacturer sampled independently the relative risks for death
and death or dependence associated with treatment with alteplase, which had a
marked impact on the ICERs in the one-way sensitivity analyses. The ERG noted
that this did not take into account the likely correlation between the outcomes
of death and death or dependence, and that the probabilistic sensitivity analysis
might not provide an accurate description of the uncertainty around the mean
costs and QALYs, although the ERG did not expect it to have a large impact on
the ICER.
3.24 The ERG conducted an exploratory sensitivity analysis by replacing the

proportion of people in the 3 health states (dependent, independent and dead)
at the end of the first phase (0 to 6 months) taken from the Lothian stroke
registry with those observed in the ECASS III trial population. Because mortality
rates were lower in the ECASS III trial, a higher proportion of patients were in
the independent state (61.54%) and a lower proportion in the dead state
(8.19%). This sensitivity analysis resulted in an ICER of 4451 per QALY gained
for alteplase compared with standard care for the 0 to 4.5-hour window
(incremental costs 698; incremental QALYs 0.157).
3.25 Full details of all the evidence are in the manufacturer's submission and the ERG
report, which are available from http://guidance.nice.org.uk/TA264

4 Consider
Consideration
ation of the e
evidence
vidence
4.1 The Appraisal Committee reviewed the data available on the clinical and cost
effectiveness of alteplase, having considered evidence on the nature of acute
ischaemic stroke and the value placed on the benefits of alteplase by people
with the condition, those who represent them, and clinical specialists. It also
took into account the effective use of NHS resources.
4.2 The Committee discussed the place of alteplase in the clinical pathway for
people who have had an acute ischaemic stroke. The Committee heard from the
clinical specialists that alteplase is routinely used in the NHS in England and
Wales in patients aged 1880 years within 4.5 hours of onset of symptoms. The
Committee was aware of the recently published third International Stroke Trial
(IST-3), an open-label trial comparing alteplase with standard care. However, the
Committee noted that the manufacturer had excluded this trial from its
submission because it provided data that were not restricted to alteplase within
its current UK marketing authorisation; specifically, the trial included patients
aged above 80 years and patients who were treated up to 6 hours after the
onset of symptoms.
4.3 The Committee heard from clinical specialists that alteplase is more effective
the earlier it is given to patients. The clinical specialists commented that, while
extending the treatment window to 4.5 hours would enable more patients to be
treated with alteplase, this might result in some patients who present early
receiving delayed treatment and therefore not benefiting from alteplase to the
extent that they might otherwise have. The clinical specialists and patient
experts emphasised the importance of treating patients with acute ischaemic
stroke as early as possible.
4.4 The Committee heard from the patient experts that an important benefit of
alteplase was its potential to reduce long-term disability caused by stroke,
which can affect the quality of life of the patient and their families, carers and
friends, and can also increase the need to adjust the patient's lifestyle and living
conditions. The Committee was aware that brain imaging must be carried out to
confirm the absence of intracranial bleeding before treatment with alteplase
can be started. However, the Committee heard from 1 patient expert that some
people with acute ischaemic stroke may not have immediate access to brain-
imaging facilities. The Committee recognised the importance of this issue, and

noted the NICE Quality Standard for Stroke, which recommends that patients
with acute stroke receive brain imaging within 1 hour of arrival at hospital. The
Committee also heard from clinical specialists that Accident and Emergency
departments of all acute-care hospitals in England and Wales should have
access to 24-hour, 7 days a week brain-imaging facilities. The Committee
recognised that patients outside the licensed indication for alteplase (under
18 years and over 80 years of age) in England and Wales may have the potential
to benefit from treatment with the technology. However, consistent with NICE
methods, the Committee was aware that it can only make recommendations
based on the current marketing authorisation for alteplase.
4.5 The Committee considered the evidence submitted by the manufacturer on the
clinical effectiveness of alteplase. The Committee noted that no clinical-
effectiveness data for the 0 to 3-hour treatment window additional to those
included in NICE technology appraisal guidance 122 were available, and that
clinical-effectiveness data for the 3 to 4.5-hour treatment window were derived
primarily from the ECASS III trial. The Committee heard from clinical specialists
that, although the trial included only a small proportion of patients from the UK,
the results of the trial were generalisable to patients receiving alteplase
treatment in England and Wales. The Committee also heard from the clinical
specialists that it was reasonable for the manufacturer to measure the
effectiveness of alteplase from analyses that adjusted for baseline differences in
potential confounding variables between the 2 treatment groups. In addition,
the clinical specialists noted that the modified Rankin scale was widely used as a
measure of disability in stroke patients in England and Wales. The Committee
concluded that the ECASS III trial was of good methodological quality and
provided robust evidence of the clinical efficacy of alteplase for the 3 to
4.5-hour treatment window.
4.6 The Committee considered the clinical effectiveness of alteplase for the 3 to
4.5-hour treatment window. The Committee noted that no statistically
significant differences in mortality, or in the composite outcome of death or
dependence, between patients randomised to alteplase or standard care were
observed at 90-day follow-up. However, the Committee also noted that a
statistically significantly higher proportion of patients in the alteplase treatment
arm achieved a favourable outcome without significant disability (modified
Rankin scale score of 0 or 1) at 90-day follow-up. The Committee therefore
concluded that alteplase administered between 3 and 4.5 hours after onset of

stroke symptoms was an effective treatment for acute ischaemic stroke because
it decreased the probability of disability.
4.7 The Committee considered the manufacturer's meta-analyses, which generated

alternative estimates of alteplase's effect on all-cause mortality and also on
death or dependence (modified Rankin scale score of 3 to 6) at 90 days for each
of the 3 treatment windows (0 to 3 hours, 3 to 4.5 hours, and 0 to 4.5 hours), and
which were used for the clinical-effectiveness parameters in the manufacturer's
economic model. The Committee noted that the trials included in the meta-
analyses for the 0 to 4.5-hour treatment window were of good methodological
quality and were sufficiently similar in terms of study design and results. The
Committee noted that there were no statistically significant differences in all-
cause mortality reported at 90 days between alteplase and placebo for any of
the 3 treatment windows. Therefore, the Committee agreed that an effect of
alteplase on improving survival has currently not been proven. The Committee
noted that a statistically significant difference in favour of alteplase was
reported for the composite outcome of death or dependence for the 0 to 3-hour
and 0 to 4.5-hour treatment windows in the manufacturer's meta-analyses. The
Committee therefore concluded that alteplase administered between 0 and
4.5 hours after onset of stroke symptoms was an effective treatment for acute
ischaemic stroke because it decreased the probability of death or dependence.
4.8 The Committee considered the evidence on adverse reactions associated with
alteplase. The Committee noted that a significantly higher proportion of
patients in the alteplase arm had symptomatic intracranial haemorrhage within
10 days compared with the placebo arm for the 3 to 4.5-hour window in the
ECASS III trial and for the 0 to 4.5-hour window in the manufacturer's meta-
analyses. However, the Committee noted that while alteplase increased the risk
of symptomatic intracranial haemorrhage, the absolute number of patients in
the ECASS III trial who had a symptomatic intracranial haemorrhage was small.
The Committee heard from the clinical specialists that symptomatic intracranial
haemorrhage is the primary cause of death within 7 days for patients receiving
alteplase treatment, and that clinicians have difficulty predicting which patients
are at high risk. The Committee also noted that the proportion of other reported
serious adverse reactions and fatal adverse reactions in the ECASS III trial up to
90 days was similar across the 2 treatment arms. The Committee concluded
that, although the increased risk of symptomatic intracranial haemorrhage
associated with alteplase is offset by significant improvements in favourable

outcomes at 90 days, symptomatic intracranial haemorrhage is an adverse event

that needs to be included in modelling of the cost effectiveness of alteplase.
4.9 The Committee considered the manufacturer's economic model, the

assumptions on which the parameters were based, and the critique and
exploratory analyses conducted by the ERG. The Committee noted that the
model structure and many of the input parameters were identical to those used
in the economic model for NICE technology appraisal guidance 122 (0 to 3-hour
window) and agreed that this approach was appropriate. With regard to the
clinical-effectiveness parameters used in the model, the Committee
acknowledged that the survival benefit associated with alteplase compared
with standard care, which resulted from a point estimate for the relative risk for
alteplase treatment and death of less than 1, was appropriately reflected in the
economic model. However, the Committee noted that the manufacturer had
assumed that the relative treatment effect of alteplase was maintained beyond
90 days up to 6 months in the model with no longer-term survival benefit
beyond this point. The Committee considered that this may have been a
conservative approach if alteplase offers a survival advantage compared with
placebo beyond 6 months, a proposition the Committee found plausible,
although not currently proven statistically, given that alteplase was associated
with a reduction in death or dependence at 90 days. The Committee was aware
that the utility values were not adjusted over time in the model, which may have
overestimated the QALYs accrued by people in the independent health state
and therefore biased the results in favour of alteplase. However, the Committee
considered that this was not a crucial limitation of the model because the ICERs
were not sensitive to changes in the utility values in the manufacturer's
sensitivity analyses, and therefore any downward adjustment over time would
have had a small impact on the ICERs. The Committee was also aware that the
manufacturer assumed that people who had a symptomatic intracranial
haemorrhage in the economic model incurred the additional one-off cost of a CT
scan but experienced no further disutility beyond that captured in the
dependent or independent health states. The Committee heard from the clinical
specialists that this assumption was reasonable. Overall, the Committee
concluded that the economic model adhered to the NICE reference case for
economic analysis and the modelling approach was reasonable.
4.10 The Committee considered the most plausible ICERs presented by the
manufacturer and also by the ERG in its exploratory analyses. It agreed that

alteplase either dominated standard care or had an ICER below 10,000 per
QALY gained depending on the time-to-treatment window considered. The
Committee noted that the results were robust for most of the deterministic
sensitivity analyses conducted by the manufacturer. The Committee also noted
that none of the additional exploratory analyses undertaken by the ERG
resulted in ICERs that varied substantially from those presented in the
manufacturer's submission. The Committee considered that patients with acute
ischaemic stroke who are admitted to hospital later (beyond 3 hours after onset
of symptoms) may have less severe stroke and so any absolute benefit of
treatment with alteplase compared with standard care may be diminished,
resulting in a higher ICER. However, the Committee noted that the ICER for the
3 to 4.5-hour treatment window was low and therefore concluded that treating
acute ischaemic stroke with alteplase within 0 to 4.5 hours of onset of stroke
symptoms was a cost-effective use of NHS resources. The Committee also
agreed with the clinical specialists that extending the time window for
treatment should not diminish the urgency with which people suspected of
having an acute ischaemic stroke should be treated.
4.11 The Committee discussed whether any equality issues required consideration in
this appraisal. The Committee was aware that extension of the licence to
4.5 hours after symptom onset may enable increased access to treatment with
alteplase for patients in remote or rural locations.
Summary of Appraisal Committee's key conclusions
TA264 Appr
Appraisal
aisal title: Alteplase for treating acute ischaemic strok
stroke
e (re
(review
view Section
of technology appr
appraisal
aisal guidance 122)
Key conclusion
Alteplase is recommended within its marketing authorisation for treating acute 1.1
ischaemic stroke in adults if:
treatment is started as early as possible within 4.5 hours of onset of stroke
symptoms, and
intracranial haemorrhage has been excluded by appropriate imaging techniques.

The Committee concluded that alteplase administered between 3 and 4.5 hours after 4.6
onset of stroke symptoms was an effective treatment for acute ischaemic stroke
because it decreased the probability of disability.
The Committee concluded that alteplase administered between 0 and 4.5 hours after 4.7
onset of stroke symptoms was an effective treatment for acute ischaemic stroke
because it decreased the probability of death or dependence.
The Committee agreed that alteplase either dominated standard care or had an ICER 4.10
below 10,000 per QALY gained depending on the time-to-treatment window
considered. The Committee concluded that treating acute ischaemic stroke with
alteplase within 0 to 4.5 hours of onset of stroke symptoms was a cost-effective use
of NHS resources.
Current pr
practice
actice
Clinical need The Committee heard from the clinical specialists that alteplase is 4.2
of patients, routinely used for the treatment of acute ischaemic stroke in the
including the NHS in England and Wales in patients aged 1880 years within
availability of 4.5 hours of onset of symptoms.
alternative
treatments
The technology
Proposed The Committee heard from the patient experts that an important 4.4
benefits of the benefit of alteplase was its potential to reduce long-term disability
technology caused by stroke, which can affect the quality of life of the patient
How and their families, carers and friends, and can also increase the need
innovative is to adjust the patient's lifestyle and living conditions.
the
technology in
its potential to
make a
significant and
substantial
impact on
health-related
benefits?

What is the A UK marketing authorisation for alteplase to treat acute ischaemic 2.1
position of the stroke within 3 hours of the onset of symptoms was granted in
treatment in September 2002. On 14 March 2012 the manufacturer received
the pathway approval from the Medicines and Healthcare products Regulatory
of care for the Agency extending the use of alteplase to within 4.5 hours of the
condition? onset of symptoms. The current marketing authorisation states that
treatment must be started as early as possible within 4.5 hours after
onset of stroke symptoms and after exclusion of intracranial
haemorrhage by appropriate imaging techniques.
Adverse The Committee noted that a significantly higher proportion of 4.8

reactions patients in the alteplase arm had symptomatic intracranial
haemorrhage within 10 days compared with the placebo arm for the
3 to 4.5-hour window in the ECASS III trial and for the 0 to 4.5-hour
window in the manufacturer's meta-analyses. However, the
Committee noted that while alteplase increased the risk of
symptomatic intracranial haemorrhage, the absolute number of
patients in the ECASS III trial who had a symptomatic intracranial
haemorrhage was small. The Committee concluded that, although
the increased risk of symptomatic intracranial haemorrhage
associated with alteplase is offset by significant improvements in
favourable outcomes at 90 days, symptomatic intracranial
haemorrhage is an adverse event that needs to be included in
modelling of the cost effectiveness of alteplase.
Evidence for clinical effectiv

effectiveness
eness
Availability, The Committee noted that no clinical-effectiveness data for the 0 to 4.5
nature and 3-hour treatment window additional to those included in NICE 4.7
quality of technology appraisal guidance 122 were available, and that clinical-
evidence effectiveness data for the 3 to 4.5-hour treatment window were
derived primarily from the ECASS III trial. The Committee concluded
that the ECASS III trial was of good methodological quality and
provided robust evidence of the clinical efficacy of alteplase for the 3
to 4.5-hour treatment window.
The Committee noted that the trials included in the meta-analyses
for the 0 to 4.5-hour treatment window were of good
methodological quality and were sufficiently similar in terms of study
design and results.

Relevance to The Committee recognised that patients outside the licensed 4.4
general indication for alteplase (under 18 years and over 80 years of age) in
clinical England and Wales may have the potential to benefit from treatment
practice in the with the technology. However, consistent with NICE methods, the
NHS Committee was aware that it can only make recommendations based
on the current marketing authorisation for alteplase.
Uncertainties The Committee noted that there were no statistically significant 4.7
generated by differences in all-cause mortality reported at 90 days between
the evidence alteplase and placebo for any of the 3 treatment windows. Therefore,
the Committee agreed that an effect of alteplase on improving
survival has currently not been proven.
Are there any Not applicable

clinically
relevant
subgroups for
which there is
evidence of
differential
effectiveness?
Estimate of From intention-to-treat analyses in the ECASS III trial, 52.4% of 3.4,
the size of the patients randomised to the alteplase treatment arm had a favourable 4.6, 4.7
clinical outcome at 90 days (a modified Rankin score of 0 or 1 [no significant
effectiveness disability]) compared with 45.2% of patients randomised to placebo
including (OR 1.34, 95% CI 1.02 to 1.76, p=0.04).
strength of The Committee concluded that alteplase administered between 3
supporting and 4.5 hours after onset of stroke symptoms was an effective
evidence treatment for acute ischaemic stroke because it decreased the
probability of disability.
The Committee noted that a statistically significant difference in
favour of alteplase was reported for the composite outcome of death
or dependence for the 0 to 3-hour and 0 to 4.5-hour treatment
windows in the manufacturer's meta-analyses. The Committee
therefore concluded that alteplase administered between 0 and
4.5 hours after onset of stroke symptoms was an effective treatment
for acute ischaemic stroke because it decreased the probability of
death or dependence.

Evidence for cost effectiv

effectiveness
eness
Availability The Committee noted that the model structure and many of the 4.9
and nature of input parameters were identical to those used in the economic model
evidence for NICE technology appraisal guidance 122 (0 to 3-hour window)
and agreed that this approach was appropriate. The Committee
concluded that the economic model adhered to the NICE reference
case for economic analysis and the modelling approach was
reasonable.
Uncertainties The Committee noted that the manufacturer had assumed that the 4.9
around and relative treatment effect of alteplase was maintained beyond
plausibility of 90 days up to 6 months in the model with no longer-term survival
assumptions benefit beyond this point. The Committee considered that this may
and inputs in have been a conservative approach if alteplase offers a survival
the economic advantage compared with placebo beyond 6 months, a proposition
model the Committee found plausible, although not currently proven
statistically, given that alteplase was associated with a reduction in
death or dependence at 90 days.

Incorporation The Committee was aware that the utility values were not adjusted 4.9
of health- over time in the model, which may have overestimated the QALYs
related accrued by people in the independent health state and therefore
quality-of-life biased the results in favour of alteplase. However, the Committee
benefits and considered that this was not a crucial limitation of the model because
utility values the ICERs were not sensitive to changes in the utility values in the
Have any manufacturer's sensitivity analyses, and therefore any downward
potential adjustment over time would have had a small impact on the ICERs.
significant and The Committee was also aware that the manufacturer assumed that
substantial people who had a symptomatic intracranial haemorrhage in the
health-related economic model incurred the additional one-off cost of a CT scan but
benefits been experienced no further disutility beyond that captured in the
identified that dependent or independent health states. The Committee heard from
were not the clinical specialists that this assumption was reasonable.
included in the
economic
model, and
how have they
been
considered?
Are there Not applicable

specific
groups of
people for
whom the
technology is
particularly
cost effective?
What are the The ICERs were robust to changes in most input parameters, except 3.18
key drivers of for the relative risks of death and death or dependence for treatment
cost with alteplase applied in the first phase of the model.
effectiveness?

Most likely The Committee agreed that alteplase either dominated standard 4.10
cost- care or had an ICER below 10,000 per QALY gained depending on
effectiveness the time-to-treatment window considered.
estimate
(given as an
ICER)
Additional factors tak

taken
en into account
Patient access Not applicable

schemes
(PPRS)
End-of-life Not applicable

considerations
Equalities The Committee was aware that extension of the licence to 4.5 hours 4.11
considerations after symptom onset may enable increased access to treatment with
and social alteplase for patients in remote or rural locations.
value
judgements

5 Implementation
5.1 The Secretary of State and the Welsh Assembly Minister for Health and Social
Services have issued directions to the NHS in England and Wales on
implementing NICE technology appraisal guidance. When a NICE technology
appraisal recommends use of a drug or treatment, or other technology, the NHS
must usually provide funding and resources for it within 3 months of the
guidance being published. If the Department of Health issues a variation to the
3-month funding direction, details will be available on the NICE website. When
there is no NICE technology appraisal guidance on a drug, treatment or other
technology, decisions on funding should be made locally.
5.2 The technology in this appraisal may not be the only treatment for acute
ischaemic stroke recommended in NICE guidance, or otherwise available in the
NHS. Therefore, if a NICE technology appraisal recommends use of a
technology, it is as an option for the treatment of a disease or condition. This
means that the technology should be available for a patient who meets the
clinical criteria set out in the guidance, subject to the clinical judgement of the
treating clinician. The NHS must provide funding and resources (in line with
section 5.1) when the clinician concludes and the patient agrees that the
recommended technology is the most appropriate to use, based on a discussion
of all available treatments.
5.3 NICE has developed tools to help organisations put this guidance into practice
(listed below). These are available on our website.
Costing template and report to estimate the national and local savings and costs
associated with implementation.
Audit support for monitoring local practice.

6 Recommendations for further research
6.1 The clinical efficacy and safety of thrombolysis with alteplase for acute
ischaemic stroke is being assessed outside of its current marketing
authorisation, specifically in patients aged up to 80 years and up to 6 hours from
onset of stroke symptoms (the third International Stroke Trial [IST-3]).

7 Related NICE guidance
Published
Clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events
(review of technology appraisal guidance 90). NICE technology appraisal guidance 210 (2010).
Prevention of cardiovascular disease. NICE public heath guidance 25 (2010).
Stroke: diagnosis and initial management of acute stroke and transient ischaemic attack (TIA).
NICE clinical guideline 68 (2008).
Lipid modification: cardiovascular risk assessment and the modification of blood lipids for the
primary and secondary prevention of cardiovascular disease. NICE clinical guideline 67 (2008).

8 Re
Review
view of guidance
8.1 The guidance on this technology will be considered for review in September
2015. The Guidance Executive will decide whether the technology should be
reviewed based on information gathered by NICE, and in consultation with
consultees and commentators.
Andrew Dillon
Chief Executive
September 2012

Appendix A: Appr
Appraisal
aisal Committee members and NICE project team
A Appraisal Committee members
The Appraisal Committee is one of NICE's standing advisory committees. Its members are
appointed for a 3-year term. A list of the Committee members who took part in the discussions for
this appraisal appears below. There are 4 Appraisal Committees, each with a chair and vice chair.
Each Appraisal Committee meets once a month, except in December when there are no meetings.
Each Committee considers its own list of technologies, and ongoing topics are not moved between
Committees.
Committee members are asked to declare any interests in the technology to be appraised. If it is
considered there is a conflict of interest, the member is excluded from participating further in that
appraisal.
The minutes of each Appraisal Committee meeting, which include the names of the members who
attended and their declarations of interests, are posted on the NICE website.
Dr Amanda Adler ((Chair)

Chair)
Consultant Physician, Addenbrooke's Hospital
Professor K
Ken
en Stein (Vice Chair)
Professor of Public Health, Peninsula Technology Assessment Group (PenTAG), University of
Exeter
Dr Ra
Rayy Armstrong
Consultant Rheumatologist, Southampton General Hospital
Dr Jeff Aronson
Reader in Clinical Pharmacology, University Department of Primary Health Care, University of
Oxford
Professor John Cairns

Professor of Health Economics Public Health and Policy, London School of Hygiene and Tropical
Medicine
Dr Mark Chakr
Chakraavarty
External Relations Director - Pharmaceuticals & Personal Health, Oral Care Europe

Mark Chapman
Health Economics and Market Access Manager, Medtronic UK
Professor F
Fergus
ergus Gleeson
Consultant Radiologist, Churchill Hospital, Oxford
Eleanor Gre
Greyy
Lay member
Dr Neil Iosson
General Practitioner
Terence LLewis
ewis
Lay Member
Professor Ruairidh Milne

Director of Strategy and Development and Director for Public Health Research at the National
Institute for Health Research (NIHR) Evaluation, Trials and Studies Coordinating Centre at the
University of Southampton
Dr Rubin Minhas
General Practitioner and Clinical Director, BMJ Evidence Centre
Dr Elizabeth Murr
Murraay
Reader in Primary Care, University College London
Dr P
Peter
eter Norrie
Principal Lecturer in Nursing, DeMontfort University
Dr John P
Pounsford
ounsford
Consultant Physician, Frenchay Hospital, Bristol
Dr John Rodriguez
Assistant Director of Public Health, NHS Eastern and Coastal Kent
Alun Roebuck
Consultant Nurse in Critical and Acute Care, United Lincolnshire NHS Trust

Cliff Snelling
Lay Member
Marta Soares
Research Fellow, Centre for Health Economics, University of York
Professor Andrew Ste

Stevvens
Professor of Public Health, Department of Public Health and Epidemiology, University of
Birmingham
Dr Nerys W
Woolacott
oolacott
Senior Research Fellow, Centre for Health Economics, University of York
B NICE project team
Each technology appraisal is assigned to a team consisting of 1 or more health technology analysts
(who act as technical leads for the appraisal), a technical adviser and a project manager.
Matthew DyDyer
er
Technical Lead
Ka
Kayy Nolan
Technical Adviser
Jerem
Jeremyy P
Powell
owell
Project Manager

Appendix B: Sources of e
evidence
vidence considered b
byy the Committee
A The Evidence Review Group (ERG) report for this appraisal was prepared by the School of Health
and Related Research (ScHARR), The University of Sheffield:
Davis S, Holmes M, Simpson E et al. Alteplase for the treatment of acute ischaemic stroke
(review of technology appraisal 122), May 2012
B The following organisations accepted the invitation to participate in this appraisal as consultees
and commentators. They were invited to comment on the draft scope. Organisations listed in I were
also invited to make written submissions. Organisations listed in II gave their expert views on
alteplase by providing a written statement to the Committee. Organisations listed in I, II and III also
have the opportunity to appeal against the final appraisal determination.
I Manufacturer/sponsor:
Boehringer Ingelheim
II Professional/specialist and patient/carer groups:
AntiCoagulation Europe UK
Association of British Neurologists
British Geriatrics Society
College of Emergency Medicine
Royal College of Nursing
Royal College of Physicians
III Other consultees:
Department of Health
Welsh Government
IV Commentator organisations (did not provide written evidence and without the right of appeal):
Healthcare Improvement Scotland

Medical Research Council
C The following individuals were selected from clinical specialist and patient expert nominations
from the non-manufacturer/sponsor consultees and commentators. They gave their expert
personal view on alteplase by providing oral evidence to the Committee.
Professor John Potter, Professor of Ageing and Stroke, University of East Anglia, nominated by
the British Geriatric Society clinical specialist
Professor Peter Sandercock, Professor of Medical Neurology, Western General Hospital,

nominated by the Association of British Neurologists clinical specialist
Dr Gavin Young, Consultant Neurologist, South Tees NHS Foundation Trust, nominated by the
NICE Clinical Guidelines clinical specialist
Joanie Scott, nominated by the Stroke Association patient expert
Robert Yexley, nominated by the Stroke Association patient expert
D Representatives from the following manufacturer/sponsor attended Committee Meetings. They

contributed only when asked by the Committee chair to clarify specific issues and comment on
factual accuracy.
Boehringer Ingelheim

Changes after publication
February 2014: minor maintenance

About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments
in the NHS in England and Wales.
This guidance was developed using the NICE single technology appraisal process.
It replaces NICE technology appraisal guidance 122 (published in June 2007).
We have produced a summary of this guidance for patients and carers. Tools to help you put the
guidance into practice and information about the evidence it is based on are also available.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the
evidence available. Healthcare professionals are expected to take it fully into account when
exercising their clinical judgement. However, the guidance does not override the individual
responsibility of healthcare professionals to make decisions appropriate to the circumstances of
the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers.

Commissioners and providers are reminded that it is their responsibility to implement the
guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have
regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a
way which would be inconsistent with compliance with those duties.
Cop
Copyright
yright
National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright
material can be downloaded for private research and study, and may be reproduced for educational
and not-for-profit purposes. No reproduction by or for commercial organisations, or for
commercial purposes, is allowed without the written permission of NICE.

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Technology appraisal guidance

NICE 2012. All rights reserved.

NICE 2012. All rights reserved. Page 2 of 37

2 The technology ............................................................................................................................................................. 5

3 The manufacturer's submission.............................................................................................................................. 6

4 Consideration of the evidence ................................................................................................................................ 15

Summary of Appraisal Committee's key conclusions ...................................................................................................... 19

6 Recommendations for further research ............................................................................................................. 27

7 Related NICE guidance............................................................................................................................................... 28

8 Review of guidance ...................................................................................................................................................... 29

Appendix A: Appraisal Committee members and NICE project team ........................................................ 30

A Appraisal Committee members ........................................................................................................................................... 30

B NICE project team ..................................................................................................................................................................... 32

Appendix B: Sources of evidence considered by the Committee ................................................................. 33

Changes after publication............................................................................................................................................. 35

About this guidance......................................................................................................................................................... 36

NICE 2012. All rights reserved. Page 3 of 37

This guidance replaces TA122.

intracranial haemorrhage has been excluded by appropriate imaging techniques.

NICE 2012. All rights reserved. Page 4 of 37

2.1 Alteplase (Actilyse, Boehringer Ingelheim) is a tissue plasminogen activator

NICE 2012. All rights reserved. Page 5 of 37

3 The manufacturer's submission

3.1 The Appraisal Committee (appendix A) considered evidence submitted by the

3.3 The clinical-effectiveness evidence in the manufacturer's submission focused on

NICE 2012. All rights reserved. Page 6 of 37

alteplase was administered within 6 hours of symptom onset. However, the

NICE 2012. All rights reserved. Page 7 of 37

3.8 The manufacturer presented a summary of adverse reactions based on

3.9 The manufacturer conducted meta-analyses to calculate the relative risks

NICE 2012. All rights reserved. Page 8 of 37

3.11 The manufacturer conducted a systematic review of published cost-

NICE 2012. All rights reserved. Page 9 of 37

NICE 2012. All rights reserved. Page 10 of 37

3.16 The manufacturer conducted a literature review to identify appropriate utility

NICE 2012. All rights reserved. Page 11 of 37

3.18 The manufacturer's base-case deterministic cost-effectiveness analysis for the

3.19 The manufacturer conducted a number of one-way sensitivity analyses on

3.20 The manufacturer's base-case deterministic cost-effectiveness analysis for the

NICE 2012. All rights reserved. Page 12 of 37

NICE 2012. All rights reserved. Page 13 of 37

3.24 The ERG conducted an exploratory sensitivity analysis by replacing the

NICE 2012. All rights reserved. Page 14 of 37

NICE 2012. All rights reserved. Page 15 of 37

NICE 2012. All rights reserved. Page 16 of 37

4.7 The Committee considered the manufacturer's meta-analyses, which generated

NICE 2012. All rights reserved. Page 17 of 37

outcomes at 90 days, symptomatic intracranial haemorrhage is an adverse event

4.9 The Committee considered the manufacturer's economic model, the

NICE 2012. All rights reserved. Page 18 of 37

Summary of Appraisal Committee's key conclusions

intracranial haemorrhage has been excluded by appropriate imaging techniques.

NICE 2012. All rights reserved. Page 19 of 37

NICE 2012. All rights reserved. Page 20 of 37

Adverse The Committee noted that a significantly higher proportion of 4.8

Evidence for clinical effectiv

NICE 2012. All rights reserved. Page 21 of 37

Are there any Not applicable

NICE 2012. All rights reserved. Page 22 of 37

Evidence for cost effectiv

NICE 2012. All rights reserved. Page 23 of 37

Are there Not applicable